The development of glioblastoma (GBM) has been hypothesized to be associated with relatively common germline alterations with limited penetrance. Recently, two genome-wide association studies (GWAS) using various single nucleotide polymorphism (SNP) array platforms have been performed in gliomas. Collaborating with the group at the University of California at San Francisco (UCSF) we recently reported that SNPs mapping near CDKN2A/B/ARF (9p21) and RTEL1 (20q13) are associated with the development of high grade astrocytomas. In a separate study of patients with gliomas, MD Anderson and European groups observed these associations as well as associations near TERT (5p15) and CCDC26/MLZE (8q24). A re-analysis of UCSF/Mayo data suggests that the RTEL1 (20q13), TERT (5p15) and CCDC26/MLZE (8q24) associations are largely restricted to patients with GBM, anaplastic astrocytoma and with oligodendroglioma, respectively - suggesting that different germline polymorphisms are associated with the development of different glioma subtypes. In this grant application we propose to further validate the germline alteration(s) within and/or near to the CDKN2A/B (9p21), TERT (5p15), RTEL1 (20q13) and CCDC26/MLZE (8q24) regions that are associated with the development of glioma, to correlate alteration status with somatic genetic and expression alterations, with pathologic variables and with clinical parameters. Our Specific Aims are: Aim 1: Perform detailed germline genetic analysis of the associated CDKN2A/B (9p21), TERT (5p15), RTEL1 (20q13) and CCDC26/MLZE (8q24) regions using three cohorts of prospectively glioma cases and controls to estimate the prevalence and relative risk of known polymorphisms and new alterations. Aim 2: Evaluate the clinical, histopathologic, and molecular pathologic relevance of the germline CDKN2A/B (9p21), TERT (5p15), RTEL1 (20q13) and CCDC26/MLZE (8q24) alterations. This application is designed to validate the alterations in each of the four regions associated with glioma development. Importantly, It will evaluate the clinical, pathologic and molecular pathologic relevance of these alterations.